pathways of lipid metabolism in marine algae co expression network bottlenecks and candidate genes for enhanced production of epa and dha in species of chromista

Although there are only a few marine-derived products currently on the market, several robust new compounds derived from marine natural products are now in the clinical pipeline, with mo

Marine Drugs

ISSN 1660-3397

www.mdpi.net/marinedrugs/

Review

Drugs and Cosmetics from the Sea

Anake Kijjoa 1,* and Pichan Sawangwong 2

1

ICBAS-Instituto de Ciências Biomédicas de Abel Salazar and CIIMAR, Universidade do Porto, 4099-003 Porto, Portugal Tel (+351) 22-2062288; Fax: (+351) 22-2062232

2

Department of Aquatic Science, Faculty of Science, Burapha University, Bangsaen, 20131 Chonburi, Thailand

*

Author to whom correspondence should be addressed; E-mail: ankijjoa@icbas.up.pt

Received: 27 April 2004 / Accepted: 13 May 2004 / Published: 25 May 2004

Abstract: The marine environment is a rich source of both biological and chemical

diversity This diversity has been the source of unique chemical compounds with the potential for industrial development as pharmaceuticals, cosmetics, nutritional supplements, molecular probes, fine chemicals and agrochemicals In recent years, a significant number of novel metabolites with potent pharmacological properties has been discovered from the marine organisms Although there are only a few marine-derived products currently on the market, several robust new compounds derived from marine natural products are now in the clinical pipeline, with more clinical development While the marine world offers an extremely rich resource for novel compounds, it also represents a great challenge that requires inputs from various scientific areas to bring the marine chemical diversity up to its therapeutic potential

Keywords: Drugs and cosmetics from the sea, marine-based drugs, anticancer agents,

immunosuppressive agents, anti-inflammatory

Introduction

Research into the pharmacological properties of marine natural products has led to the discovery of many potently active agents considered worthy of clinical application The marine environment is an exceptional reservoir of bioactive natural products, many of which exhibit structural/chemical features not found in terrestrial natural products [1] Marine organisms have evolved biochemical and physiological mechanisms that include the production of bioactive compounds for such purposes as reproduction, communication, and protection against predation, infection and competition [2] Because

of the physical and chemical conditions in the marine environment, almost every class of marine organism exhibits a variety of molecules with unique structural features

But beyond the chemical diversity, the sea also provides amazing biological diversity Among 34 fundamental phyla of life, 17 occur on land whereas 32 occur in the sea [with some overlap] From the fundamental point of view of biodiversity, the ocean is far more diverse and really would have been the better place to start to develop a natural Pharmacy

To date, researchers have isolated approximately 7000 marine natural products, 25 percent of which are from algae, 33 percent from sponges, 18 percent from coelenterates (sea whips, sea fans and soft corals), and 24 percent from representatives of other invertebrate phyla such as ascidians (also called tunicates), opisthobranch molluscs (nudibranchs, sea hares etc), echinoderms (starfish, sea cucumbers

etc) and bryozoans (moss animals) A simplistic analysis of these data reveals that as the search for

“Drugs from the Sea” progresses at the rate of a 10 percent increase in new compounds per year, researchers are concentrating their efforts on slow-moving or sessile invertebrate phyla that have soft

bodies, and lack of spines or a shell, i.e animals that require a chemical defence mechanism [3]

Actually, there was a first, albeit very small, wave of marine-derived drugs that resulted in several

products currently on drugstore shelves Back in the 1950s, Bergmann et al isolated several

nucleosides from the Caribbean sponge Tethya crypta (Tethylidae) Two of these, spongothymidine (1)

and spongouridine (2) contained a rare arabinose sugar rather than ribose, which is a quite ubiquitous sugar in nucleosides This discovery led researchers to synthesize analogues, Ara-A (3, Vidarabine®, Vidarabin Thilo®) and Ara-C (4, Cytarabine, Alexan®, Udicil®), which improved antiviral activity

Currently, these are the only marine related compounds in clinical use [4]

N N

O

OH

CH 2 OH O H O

O

CH 3

N N

O

OH

CH 2 OH O H O

O

CH 3

N N

O

OH

CH 2 OH O H

N N

N

H 2

N N

O

OH

CH 2 OH O H

NH 2

O

Considering the importance of nucleoside-analogues in antiviral and anticancer therapy, e.g.,

3’-azido-3’-deoxythymidine (AZT, Zidovudin), the original discovery of Bergmann can be considered

one of immense significance

Compounds in Preclinical and Clinical Evaluation

In recent years many marine natural products which are promising candidates for new drugs have

been discovered (Table 1):

Table 1 Potential therapeutic compounds from marine sources

Bryostatin1 Bryozoan Gulf of California

Dolastatin 10 Sea hare Indian Ocean

HIV Cyclodidemniserinol trisulfate Tunicate Palau

Lamellarin a 20 sulfate Tunicate Australia

However, as the relevant clinical data were not available for most of the compounds indicated in

Table 1, only some of them shall be mentioned in detail in this review

Bryostatin 1

The bryostatins are macrocyclic lactones isolated from the marine bryozoan Bugula neritina

(Bugulidae) Bryostatin 1 is one of the most abundant and best studied compounds of this series It was

originally described on the basis of inhibiting growth in murine P388 lymphocytic leukemia cells at

subnanomolar concentrations A range of properties have subsequently been described including

activation of T-cells, immunomodulation and stimulation of haematopoietic progenitor cells However,

only many years after its discovery was the molecular site of action of this compound identified

Bryostatin 1 was found to bind to protein kinase C with high affinity, which may be the mechanistic basis for both observed anticancer and immunostimulating activities [5]

O

O

CH 3 O

O

CH 3 OH

CH 3

CH 3

O O

CH 3 O

O

OH H O

C

H 3

O

C

H 3

CH 3

O H

H

H H

H

H

OMe

Bryostatin 1 has been licensed to Bristol-Mayers Squibb It has just completed Phase I clinical

trials in the United States and is now being tested in Phase II human clinical trials by the NCI under an

agreement with Bristol-Mayers However, bryostatin 1 is not effective in cancer treatment by itself

but it seems to enhance the activity of such chemotherapies as taxol and cisplatin Bryostatin 1 may be used in tandem with cancer treatments that respond to taxol, such as breast, ovarian and lung cancers

Didemnin B

Didemnin B is one of a number of related depsipeptides isolated from the Caribbean tunicate

Trididemnum solidum (Didemnidae) It was later found to display antineoplastic, antiviral and

subsequently immunosuppresive activities [6] Mechanistically, didemnin B acts at the GTP-binding protein elongation factor 　 [5] This compound, though, is too toxic to be useful as antiviral or immunosuppressive agent, it has been in Phase I clinical trials as an anticancer agent Phase II clinical trials are underway

O H

O H

OH H NH O H N

O N

N OH

H O

O

H O O

H N

OMe

O

N H

O H NH O H O

C

CH 2

A close relative of didemnin B - dehydrodidemnin B, isolated from a Mediterranean tunicate

Aplidium albicans, is currently in Phase II studies in the United States and Europe, to determine its

anticancer properties PharmaMar SA of Spain owns the rights to the compound, which has been

shown to be six times more effective than didemnin B in animal tests

Dolastatin 10

Dolastatin 10 is a linear peptide isolated from the sea hare Dollabella auricularia from the Indian

Ocean and is a well known antitumour agent with ED50 = 0.046 ng/ml against P 388 cells It displayed unprecedented potency in experimental antineoplastic and tubulin assembly systems Dolastatin 10 is

in Phase I clinical trials as anticancer agent for use in the treatment of breast and liver cancers, solid tumours and leukemia [7]

Me N Me

N H O

N Me O

N

O OMe

N H

N

Discodermolide

Discodermolide is a polyhydroxylated lactone, isolated from the deep-sea sponge Discodermia ssp

Descodermolide is an immunosuppresive and cytotoxic agent [8] The study of its mechanism has

revealed that discodermolide was able to stabilize microtubules In 1998 Novartis Pharma AG

licensed this compound for development as a candidate agent for treatment of cancers

O O

OH

OH

OH

OH

NH 2 O

Ecteinascidin-743 (ET-743)

Ecteinascidin-743 or ET-743 is a tetrahydroisoquinoline alkaloid derived from the colonial tunicate

Ecteinascidia turbinata, a sea squirt that lives in clusters in the Caribbean and Mediterranean seas

Early on, the compound demonstrated very potent activity against a broad spectrum of tumour types in animal models [9] The initial sets of Phase I trials for this compound were completed in 1998, with the objective of finding the maximum tolerated dose and studying any possible toxicities The studies identified a safe, tolerable dose and demonstrated the feasibility of applying it in multiple cycles Early trial results have shown promising activity of ET-743 in the treatment of advanced soft tissue sarcoma (STS), osteosarcoma and metastatic breast cancers

Development of ET-743 was followed with interest by the medical community, as anti-tumour activity was observed in all Phase I programs, which were conducted on patients with advanced-stage breast, colon, ovarian and lung cancers, melanoma, mesothelioma and several types of sarcoma Phase

II studies with ET-743 are being performed at 13 different centres in France, Belgium, the Netherlands, the United Kingdom and the United States, in cooperation with assisting groups such as the European Organisation for Research and Treatment of Cancer (EORTC) The European Commission’s Biomed

II demonstration program provided partial funding for six of the European studies in 1999

NH

N N

OMe O

H O

O O O O

O H MeO

H H H OH S H

H H H

Recent research indicates that ET-743 may even be able to prevent tumours from becoming drug-resistant in the first place It was found that ET-743 prevents the formation of P-glycoprotein, a protein associated with multidrug-resistant tumours [10] P-glycoprotein is a membrane protein that transports toxins such as chemotherapy agents out of the cancer cells, preventing the chemotherapy drugs from destroying the tumour Previous studies have indicated that when tumours are exposed to chemotherapy agents, they quickly boost the activity of the MDR1 gene, which is responsible for the formation of P-glycoprotein By interfering with that process, ET-743 may keep the tumour cells vulnerable to chemotherapy Even if ET-743 is not proven effective on its own, it may become a key ingredient in chemotherapy “cocktails” to prevent tumours from developing resistance to drugs currently used

Kahalaide F

Kahalaide F is a depsipeptide discovered in Elysia rufescens, a marine mollusc found in Hawaii

Studies to determine the mechanism of action of Kahalaide F showed that, in certain experimental systems, it caused a disruption of lysosomal membranes and consequently the formation of large vacuoles This mechanism is unique among anticancer agents and may cause increasing acidification

of the intra-cellular space, a stimulatory event that initiates a pathway for apoptosis [11] In addition,

Kahalaide F leads to an inhibition of erb 2 transmembrane tyrosine kinase activity and inhibits TGF–a

gene expression

The pattern of Kahalaide F cytotoxicity was distinct from any of the other standard

chemotherapeutic agents Kahalaide F showed in vitro and in vivo selectivity for prostate-derived cell

lines and tumours It is further selective for hormone-independent prostate tumour cells, which generally represent the more aggressive and harder to treat type of prostate cancer Phase I clinical trials in patients with androgen-independent prostate cancer have begun

N

O

N H

O

N H

O

NH O N O

N O O

NH

O N H

O

N H

N

H 2 O

O N H O

N

NH

It is interesting to note that the majority of the compounds under clinical trials described so far are either cytotoxic or immunosuppresive agents However, as the advance in mechanism-based bioassays continues, other pharmacologically active marine natural products have been discovered These include:

Ziconitide (Conotoxin MVIIV)

Ziconitide is a 25 aminoacid peptide from the venom of a predatory snail Conus magnus It acts by

binding to and inhibiting presynaptic calcium channels, thereby preventing neurotransmitter release

[12] It is licensed by Elan Pharmaceuticals under the name Prialt

Prialt blocks nerve impulses in a key region of the spinal cord, where pain fibers from the body

connect with the nerve cells that send pain to the brain This is why Prialt, which is 50 times more potent than morphine, is so exquisitely precise and does not cause the adverse effects of opiates It stops pain messages from getting through while allowing the rest of the nervous system to function normally

However, it would be inaccurate to assume that all of the biologically active compounds being tested are toxic As the secondary metabolites from marine organisms show diverse structural types, it

is expected that they should have biological activities across the board These compounds are:

Manoalide

Manoalide is a sesquiterpenoid isolated from the Indo-Pacific sponge Luffariella variabilis It is a

potent analgesic and anti-inflammatory agent Manoalide is by far the best characterised PLA2

inhibitor from natural sources At low concentrations manoalide inhibited calcium channels with no

effect on phosphoinositide metabolism Manoalide was licensed by Allergan Pharmaceuticals who

took the compound through Phase I clinical trials for the treatment of psoriasis, then launched a medicinal chemistry program with it Though no pharmaceutical based on manoalide has yet reached the drugstores, manoalide itself is commercially available as a standard probe for PLA2 inhibition [13]

O

O O H

O H

O

Pseudopterosins

The pseudopterosins are tricyclic diterpene glycosides isolated from the Caribbean sea whip

(gorgonian) Pseudopterogorgia elisabethae (Gorgoniidae) They are potent anti-inflammatory and

analgesic agents and appear to inhibit eicosanoid biosynthesis by inhibition of both PLA2 and 5-lipoxygenase Interestingly, the pseudopterosins are found to inhibit only PMN-PLA2, and not PLA2

from other sources It is also thought that the cell type selectivity of the pseudopterosins may well be a function of the glycoside moiety and a novel example of drug targeting [13]

O

O

OR 3

OR 2

OR 1 H

CH 3

OR 4 H

Pseudopterosin A : R 1 =R 2 = R 3 = R 4 = H Pseudopterosin B : R 1 = Ac, R 2 = R 3 = R 4 = H Pseudopterosin C : R 2 = Ac, R 1 = R 3 = R 4 = H Pseudopterosin D : R 3 = Ac, R 1 = R 2 = R 4 = H

1 2

3 4

5 6 7 8

9 10

11

20

12 13

14 15

16

18

19

17

The pseudopterosins have been licensed to a small pharmaceutical firm, OsteoArthritis Sciences Inc , for medical use as potential anti-inflammatory drugs The company has completed preclinical

tests of one of pseudopterosins, a potent tropical anti-inflammatory compound, and filed an Investigational New Drug (IND) application with the U.S food and Drug Administration Clinical trials on human subjects for irritant contact dermatitis are anticipated

However, the pseudopterosins extract has found its way to the marketplace It is used as an additive

to prevent irritation caused by exposure to the sun or the chemicals in the Estée Lauder cosmetic skin care product, Resilience® [14]

Acknowledgements

We wish to thank Fundação para a Ciência e Tecnologia (FCT) of Portugal, POCTI (QCA III) and FEDER for support

References

1 Carté, B K.; Biomedical Potential of Marine Natural Products Biosciences 1996, April, 271-286

2 Halvorson, H O Aquaculture, Marine Sciences and Oceanography: A Confluence Connection

New Engl J Higher Ed Econ Dev 1998, 13, 28-42

3 Faulkner, D J.; Chemical Riches from the Ocean Chem Brit 1995, 680-684

4 Scheuer, P J.; Marine Metabolites as Drug Leads-Retrospect and Prospect: In Biochemical Aspects of Marine Pharmacology Lazarovici, P.; Spira, M E.; Zlotkin, Eliahu Eds.; Alaken, Inc.:

Fort Collins, Colorado, 1996; pp 1-12

5 de Vries, D J.; Beart, P M.; Fishing for Drugs from the Sea: Status and Strategies TiPS 1995, 16,

275-279

6 Rinehart, K L., Kishore, V., Bible, K C., Sakai, R., Sullins, D W.; Li, K.M.; Didemnins and

Tunichlorin: Novel Natural Products from the Marine Tunicate Trididemnum solidum J Nat

Prod 1988, 51, 1-21

7 Yamada, K, Okija, M., Kigoshi, H.; Suenaga, K.; Cytotoxic Substances from Opisthobranch

Molluscs: In Drugs From The Sea; Fusetani, N., Ed.; Karger AG: Basel, 2000; pp 59-73

8 Gunasekera, S P., Gunasekera, M., Longley R E., Schulte, G K J Org Chem 1990, 55,

4912-4915

9 Rinehart, K L.; Antitumor Compounds from Tunicates Med Res Rev 2000, 20, 1-27

10 Zewail-Foote, M.; Hurley, L.H Ecteinascidin 743: A Minor Groove Alkylator that Binds DNA

Toward the Major Groove J Med Chem 1999, 42, 2493-2497

11 Hamann, M T.; Scheuer, P J Kahalide F; A Bioactive Depsipeptide from the Sacoglossan

Mollusk Elisia refescens and the Green Alga Bryopsis sp J Am Chem Soc 1993, 115,

5825-5826

12 Oliveira, B M., Gray, W R., Zeikus, R., McIntosh, J M., Varga, J., Revier, J., de Santos, W.;

Cruz, L J; Peptide Neurotoxins from Fish-Hunting Cone Snails Science 1985, 230, 1338-1343

13 Potts, B C M.; Faulkner, D J.; Phospholipase A2 Inhibitors from Marine Organisms J Nat

Prod 1992, 55, 1701-1717

14 Rouhi, A M.; Supply Issues Complicate Trek of Chemicals from the Sea to Market C&EN, 1995,

November 20, 42-44

© 2004 by MDPI (http://www.mdpi.org) Reproduction is permitted for noncommercial purposes